Numerous skin disorders result in the hypertrophy of the stratum corneum, an occurrence also described as hyperkeratinization. The thickened superficial layer of the epidermis results in scale-like plaques on the surface of the skin. These scaly plaques are the manifestation of a group of disorders termed ichthyoses because of their resemblance to fish scales. The plaques may be symptoms of a skin disorder and accordingly prohibit the treatment of these disorders originating in underlying layers of the skin. The hypertrophied skin layer may also harbor infections within itself.
Typical examples of ichthyoses which do not have known etiologies include psoriasis, pityriases, rosacea, and seborrheic dermatitis. These disorders are treated symptomatically with keratolytic agents to remove the plaques and with glucocorticoids to alleviate inflammation. Dermaphytoses are ichthyoses caused by fungal infections. The hyphae and spores are confined to nonviable portions of tissue and thus proliferate in the hyperkeratinized tissues of skin, hair, and nails. Examples of typical dermaphytoses include tinea capitis (cradle cap), tinea pedis (athlete's foot), and tinea unguium. These disorders are treated with anti-fungal agents, and topically with keratolytic agents to remove the cornified and infected layer.
Skin disorders may also be caused by a hormonal imbalance. Such an imbalance may cause increased levels of testosterone, as in the onset of puberty. Testosterone is reduced to dihydrotestosterone (DHT) in target tissues, including the sebaceous glands. In the common dermatological disorder acne, DHT binds to receptors in the pilosebaceous complex and stimulates excessive sebum secretion. The sebum acts as a nutrient for bacteria such as Propionibacterium acnes, which infect the sebaceous gland and lead to an inflammatory response and abnormal cornification of the skin. Acne is typically treated with antibacterial and antiseptic agents, and also with keratolytic agents, such as salicylic acid or retinoic acid, to remove the hyperkeratinized tissue.
The terms eczema and dermatitis are generally used names for severe inflammation of the skin, usually with redness, swelling, oozing, rusting or scaling of lesions which are usually itchy. Eczema may take the form of contact dermatitis (due to skin contact with the cause) or atopic dermatitis in individuals who are "atopic" or allergic by nature. If the scalp is involved the disorder is known as seborrheic dermatitis. Dermatitis can be caused by chemicals, plants, shoes, clothing, metal compounds and even medicines used to treat dermatitis. In atopic dermatitis environmental temperature, humidity changes, bacterial skin infections, airborne allergens and garments, e.g., wool, may all bring about dermatitis.
Alopecia areata is a common condition that results in the loss of hair on the scalp and elsewhere. It usually starts with one or more small, round, smooth patches and occurs in males and females of all ages, but young persons are affected most often. Most patients just lose one spot of hair, or two to three small spots, but it is possible to lose all scalp hair (alopecia totalis), or, even more rarely, every hair on the body (alopecia universalis). Modern immunological research is showing that alopecia areata is probably an autoimmune disorder, one in which the body forms antibodies against some part of the hair follicle (a type of "self-allergy").
Skin disorders, such as those described above, create aesthetic disturbances, treatment of which sometimes are regarded as cosmetic processes. They may be treated using known medications, however, it is common knowledge that cosmetic products, e.g., soaps, lotions, and shampoos, also include ingredient to combat conditions such as acne, dandruff, seborrhea and androgenic alopecia.
Azelaic acid (AZA) is a naturally occurring nine carbon straight chain molecule with two terminal carboxyl groups. AZA is an anti-keratinizing agent, displaying antiproliferative effects on keratinocytes and modulating the early and terminal phases of epidermal differentiation (Passi, et al. G. Ital. Dermatol. Venerol. 1989, 124(10):455-463). AZA is a competitive inhibitor of the reduction of testosterone to dihydrotestosterone, and as such is supposed to reduce the production of sebum in the sebaceous gland. Furthermore, recent investigations have demonstrated that AZA and sebacic acid also have anti-bacterial and anti-fingal properties. Structure-activity relationship studies have revealed that these effects are retained when the .alpha.,.omega.-dicarboxylic acid has a backbone of about 6 to about 14 carbons.
Thus, azelaic acid, and other .alpha.,.omega.-dicarboxylic acids, may be used as therapeutic agents in the treatment of skin disorders; however, treatment of the above disorders is hindered by the low bioavailability of such therapeutic agents. Dicarboxylic acids such as azelaic acid are very polar due to the two carboxyl groups. Because of this polarity, skin penetration is very low. In addition, the presence of the acid functional group lowers the pH, which may cause irritation of the skin. Only high concentrations of the azelaic acid in topical preparations (20%) are effective in treating acne. To demonstrate how weak is the therapeutic effect of AZA lotion, a 20% preparation was effective only after 3-6 months of topical application, twice daily. See, A. Fitton and K. L. Goa, Drugs 41: 780-798 (1991). Furthermore, in additional studies topical administration of AZA failed to induce specific changes in sebum composition, sebum excretion rate and the size of sebaceous glands (See for example Mayer-da-Silva et al, 1989, Acta Derm. Venereol. Suppl. (Stockholm) 143: 20-30). Other dermatological agents also comprise a polar functional group, such as a carboxy or hydroxy group, rendering their skin penetration relatively low. Thus there remains a need to increase the efficacy of these drugs in the treatment of skin disorders in which the availability of the drugs through topical application is improved.
.alpha.,.omega.-Dicarboxylic acids, and their mercapto, ester and salt derivatives have been used in the treatment of a variety of skin disorders and/or conditions. Relevant discussions on their uses may be found in the following references.
Hill et al in U.S. Pat. No. 4,034,077 teaches the use of a composition comprising sebacic acid for the treatment of skin irritation and the prevention of diaper rash in which the dicarboxylic acid acts as a barrier between the urine and the skin and also neutralizes ammonia. It does not teach the use of sebacic acid in the treatment of any endogenous disorder, including any form of ichthyosis, or any hormonal imbalance.
Nazzaro-Porro (U.S. Pat. No. 4,292,326) discloses a method of treating hyperpigmentary dermatoses with dicarboxylic acids, such as azelaic acid. These acids, along with their mono- and dimercapto derivatives, are used for their ability to normalize skin color by inhibiting melanogenesis. Nazzaro-Porro (U.S. Pat. No. 4,386,104) teaches the use of the same compounds for the treatment of acne. It also teaches adding a small amount of keratolytic agent to the composition. Nazzaro-Porro (U.S. Pat. No. 5,385,943) also discloses the use of topically applied preparations, comprising an ester of a dicarboxylic acid cleavable by skin enzymes, particularly a glycerol ester, for treatment of presbyderma of the aging skin.
Thornfeldt (U.S. Pat. No. 4,885,282) discloses a treatment of hyperhydrosis, ichthyosis and wrinkling of the skin by means of a mono- or di-carboxylic acids (4-18C), along with their mercapto derivatives, salts and esters. The use of alkyl, polyol, oligosaccharide and polysaccharide esters, and specifically glycerol, polyethylene glycol, polypropylene glycol and sucrose esters of the respective mono- or di- carboxylic acids is described. UK Pat. Appl. No. GB 2,285,805 teaches the use of esters of dicarboxylic acids with vitamins A, E and D as antitumor agents. Chamness (U.S. Pat. No. 5,547,989) teaches a topical composition comprising dicarboxylic acids (7-13C and specifically AZA), salts and esters thereof for treating corns and calluses. However, no specific ester is claimed or demonstrated by an example.
Sugibayashi et al (Chem. Pharm. Bull., 36(4): 1519-1528 (1988)) teaches the use of penetration enhancers for the model compound indomethacin. It discloses the use of salicylates as enhancers because of their ability to soften and dissolve the stratum corneum. They teach the use of salicylates as keratolytic agents to remove the outer layer of cells, which then allows easier penetration of the desired compound.
Luedders, (U.S. Pat. No. 4,299,826) teaches a physical mixture of the antibacterial agent erythromycin, with the penetration enhancer diisopropyl sebacate. Luedders teaches that this additive increases the penetration of erythromycin. DE 4213419 discloses a salicylic acid ester derivative of azelaic acid in a glycerin trinitrate carrier for pharmaceutical applications. The low pH of the salicylic acid ester tends to irritate the treated tissues.
Known references disclose complex esters of straight chain dicarboxylic acids. In U.S. Pat. No. 5,494,924, Cavazza et al. teaches the treatment of ichthyoses using complex esters of .alpha.,.omega.-dicarboxylic acids and carnitine. Bilibin et al. (USSR Pat. No. 761,452) teaches the synthesis of straight carbon chain .alpha.,.omega.-dicarboxylic acids esterified by reaction with p-hydroxy benzoates, which are used as monomers for the formation of liquid crystalline polymers. In U.S. Pat. No. 3,660,467, Gould teaches phenoxy phenyl esters of .alpha.,.omega.-dicarboxylic acids for use as synthetic lubricants and heat transfer fluids. Portnoy et al (Chemical Engineering Data Series, 1958, 3: 287-293) teaches the use of phenyl .alpha.,.omega.-dicarboxylates in the development of nonspreading lubricant oils. Although the aforementioned an describes compounds comprising esterified .alpha.,.omega.-dicarboxylic acids, there is no discussion of the use of these compounds in treatment of skin disorders.
Thus, there remains a need to provide therapeutic agents for the treatment of skin disorders which demonstrate improved efficacy and reduced irritation over the agents available in the prior art.